Abstract
WNT signaling has been implicated in both embryonic and postnatal bone formation. However, the pertinent WNT ligands and their downstream signaling mechanisms are not well understood. To investigate the osteogenic capacity of WNT7B and WNT5A, both normally expressed in the developing bone, we engineered mouse strains to express either protein in a Cre-dependent manner. Targeted induction of WNT7B, but not WNT5A, in the osteoblast lineage dramatically enhanced bone mass due to increased osteoblast number and activity; this phenotype began in the late-stage embryo and intensified postnatally. Similarly, postnatal induction of WNT7B in Runx2-lineage cells greatly stimulated bone formation. WNT7B activated mTORC1 through PI3K-AKT signaling. Genetic disruption of mTORC1 signaling by deleting Raptor in the osteoblast lineage alleviated the WNT7B-induced high-bone-mass phenotype. Thus, WNT7B promotes bone formation in part through mTORC1 activation.
Highlights
WNT proteins are a family of signaling molecules that control cell proliferation, fate decision, polarity and migration throughout metazoan evolution [1]
Bone tissue regeneration deteriorates with age, and tremendous unmet medical needs exist for safe and effective strategies to stimulate bone formation in older individuals commonly inflicted with osteoporosis or osteopenia
The present study reports that WNT7B potently enhances bone formation through activation of mTORC1 in the mouse
Summary
WNT proteins are a family of signaling molecules that control cell proliferation, fate decision, polarity and migration throughout metazoan evolution [1]. Deregulation of WNT signaling is frequently associated with human diseases [3]. WNT signaling was first associated with bone diseases by the finding that loss-of-function mutations in the WNT co-receptor LRP5 cause osteoporosispseudoglioma syndrome (OPPG) (Gong et al, 2001). Deficiency in the secreted WNT inhibitor SOST, or mutations in LRP5 rendering it refractory to the WNT inhibitors such as SOST or DKK1, results in high bone mass in patients [4,5,6,7,8,9]. Mutations in WTX, an inhibitor of WNT/b-catenin signaling, were shown to cause X-linked sclerosing bone dysplasia known as OSCS in humans [10,11]. Genetic evidence from both humans and mice supports the importance of WNT signaling in bone formation
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